Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT1B receptor gene in 273 nuclear families from a multi-centre sample

Hawi, Ziarih; Dring, Megan; Kirley, Aiveen; Foley, Debra L.; Kent, Lindsey; Craddock, Nick; Asherson, Philip; Curran, Sarah; Gould, Alison L.; Richards, Sandra; Lawson, Deborah C.; Pay, Helen; Turic, Dragana; Langley, Kate; Owen, Michael John; O’Donovan, Michael; Thapar, Anita; Fitzgerald, Michael; Gill, Michael

doi:10.1038/sj.mp.4001048

Cited by 149 publications

(114 citation statements)

References 33 publications

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“…It is not known if drugs that enhance the locomotor stimulant effects of methylphenidate in the experimental animal can improve its therapeutic effect in patients with ADHD, but, in view of the widespread use of methylphenidate in ADHD, the study of potential therapeutic benefits of the combination of 5-HT 1B receptor agonists with methylphenidate merits investigation. Interestingly, 5-HT 1B receptor polymorphisms have been associated with some forms of ADHD (Hawi et al, 2002;Smoller et al, 2006), supporting the hypothesis that 5-HT 1B receptors could be a target for the development of drugs active on ADHD.…”

Section: Figurementioning

confidence: 62%

5-HT1B Receptor-Mediated Serotoninergic Modulation of Methylphenidate-Induced Locomotor Activation in Rats

Borycz

Zapata

Quiroz

et al. 2007

Neuropsychopharmacol

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Previous studies have shown that the dopamine (DA) uptake blocker methylphenidate, a psychostimulant widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), prevents the neurotoxic effects of the highly abused DA releaser methamphetamine. However, there is a lack of information about the pharmacological interactions of these two drugs at the behavioral level. When systemically administered within an interval of 2 h, previous administration of methylphenidate (10 mg/kg, intraperitoneal (i.p.)) did not modify locomotor activation induced by methamphetamine. On the other hand, previous administration of methamphetamine (1 mg/kg, i.p.) markedly potentiated methylphenidate-induced motor activation. With in vivo microdialysis experiments, methamphetamine and methylphenidate were found to increase DA extracellular levels in the nucleus accumbens (NAs). Methamphetamine, but not methylphenidate, significantly increased the extracellular levels of serotonin (5-HT) in the NAs. Methamphetamine-induced 5-HT release remained significantly elevated for more than 2 h after its administration, suggesting that the increased 5-HT could be responsible for the potentiation of methylphenidate-induced locomotor activation. In fact, previous administration of the 5-HT uptake blocker fluoxetine (10 mg/kg, i.p.) also potentiated the motor activation induced by methylphenidate. A selective 5-HT 1B receptor antagonist (GR 55562; 1 mg/kg), but not a 5-HT 2 receptor antagonist (ritanserin; 2 mg/kg, i.p.), counteracted the effects of methamphetamine and fluoxetine on the motor activation induced by methylphenidate. Furthermore, a 5-HT 1B receptor agonist (CP 94253; 1-10 mg/kg, i.p.) strongly and dose-dependently potentiated methylphenidate-induced locomotor activation. The 5-HT 1B receptor-mediated modulation of methylphenidate-induced locomotor activation in rat could have implications for the treatment of ADHD.

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Section: Figurementioning

confidence: 62%

5-HT1B Receptor-Mediated Serotoninergic Modulation of Methylphenidate-Induced Locomotor Activation in Rats

Borycz

Zapata

Quiroz

et al. 2007

Neuropsychopharmacol

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“…Given previous findings of preferential paternal transmission bias with other candidate genes in ADHD, [23][24][25][26] TDTPHASE 27 was used to test transmissions from fathers and mothers separately. The proportions of transmitted vs nontransmitted alleles between ADHD subtypes and comorbid groups were compared using w 2 tests.…”

Section: Methodsmentioning

confidence: 99%

Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD

et al. 2005

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Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable, neurodevelopmental disorder with onset in early childhood. Genes involved in neuronal development and growth are, thus, important etiological candidates and brain-derived neurotrophic factor (BDNF), has been hypothesized to play a role in the pathogenesis of ADHD. BDNF is a member of the neurotrophin family and is involved in the survival and differentiation of dopaminergic neurons in the developing brain (of relevance because drugs that block the dopamine transporter can be effective therapeutically). The common Val66Met functional polymorphism in the human BDNF gene (rs 6265) was genotyped in a collaborative family-based sample of 341 white UK or Irish ADHD probands and their parents. We found evidence for preferential transmission of the valine (G) allele of BDNF (odds ratio, OR ¼ 1.6, P ¼ 0.02) with a strong paternal effect (paternal transmissions: OR ¼ 3.2, P ¼ 0.0005; maternal transmissions: OR ¼ 1.00; P ¼ 1.00). Our findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The transmission difference between parents raises the possibility that an epigenetic process may be involved. Keywords: attention deficit hyperactivity disorder; association study; neurotrophic factor; polymorphism Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 2-5% of school-aged children with more boys diagnosed than girls. 1 It is characterized by marked and pervasive inattention, overactivity and impulsiveness and causes significant social, educational and psychological problems. Quantitative genetic research over the last decade, from family, twin and adoption studies has firmly established that ADHD has a significant genetic contribution. 2 The medications most often used for ADHD are psychostimulants including methylphenidate and dexamphetamine. Precise therapeutic mechanisms of these drugs in ADHD remain unclear, although methylphenidate is known to inhibit the dopamine transporter. As a result, most candidate gene studies to date have focused on the dopamine system. 3 Positive findings have been successfully replicated for variants in the D4 dopamine receptor (DRD4), 4 D5 dopamine receptor (DRD5) 5 and the dopamine transporter (DAT1). 6 These family-based meta-analyses each report small effect sizes with odds ratios of less than 1.5, indicating that if they are true susceptibility variants for ADHD their contribution to the overall phenotype is small. Given that ADHD is a neurodevelopmental disorder, genes involved in neuronal development and growth represent an important set of candidates for involvement in the pathogenesis. One such candidate that has been postulated to play a role in ADHD is BDNF (MIM 113505). 7 The gene encoding BDNF is located at 11p13 and codes for a precursor peptide (proBDNF), which is proteolytically cleaved to form the mature protein. Only one nonsynonymous polymorphism in the human BDNF gene (rs 6265) has been identified, a single nucleotide polymorph...

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“…In particular, replicated associations have been reported with the dopamine D4 and D5 receptors (DRD4 and DRD5), 4,[11][12][13] the dopamine transporter (DAT1) and the serotonin 1B receptor (5HT1B) 14,15 genes. Although the identification of such consistent findings is unusual in the study of human behavioural disorders, uncertainties remain over their validity and further evidence is required before we can be confident that the reported findings represent true genetic associations.…”

Section: Introductionmentioning

confidence: 92%

“…Although the identification of such consistent findings is unusual in the study of human behavioural disorders, uncertainties remain over their validity and further evidence is required before we can be confident that the reported findings represent true genetic associations. For the known markers that are currently reported to be associated with ADHD, odds ratios have been estimated at 1.4, 1.16, 1.4 and 1.48 for DRD4, 11 DAT1, 5 DRD5 (unpublished data) and 5HT1B, 14 respectively, on the basis of meta-analyses of available data. Of these, the lowest odds ratio estimate comes from the meta-analysis of a VNTR polymorphism within the 3 0 -untranslated region of DAT1, in which both linkage and association has been reported between the 10-repeat allele and ADHD (w 2 ¼ 3.45, P ¼ 0.06, OR ¼ 1.16).…”

Section: Introductionmentioning

confidence: 99%

The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample

Chen

Mill

et al. 2003

Mol Psychiatry

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Genetic variation of the dopamine transporter gene (DAT1) is of particular interest in the study of attention-deficit hyperactivity disorder (ADHD), since stimulant drugs interact directly with the transporter protein. Association between ADHD and the 10-repeat allele of a 40-bp VNTR polymorphism that lies within the 3 0 -UTR of DAT1 was first reported in 1995, a finding that has been replicated in at least six independent samples from Caucasian populations. We analysed the DAT1 polymorphism in a sample of 110 Taiwanese probands with a DSM-IV diagnosis of ADHD and found evidence of increased transmission of the 10-repeat allele using TRANSMIT (v 2 ¼ 10.8, 1 d.f., p ¼ 0.001, OR=2.9, 95% CI 1.4-6.3). These data give rise to a similar odds ratio to that observed in Caucasian poplulations despite a far higher frequency of the risk allele in this Taiwanese population; 82.3% in the un-transmitted parental alleles and 94.5% in the ADHD probands. These data support the role of DAT1 in ADHD susceptibility among Asian populations.

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Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT1B receptor gene in 273 nuclear families from a multi-centre sample

Cited by 149 publications

References 33 publications

5-HT1B Receptor-Mediated Serotoninergic Modulation of Methylphenidate-Induced Locomotor Activation in Rats

5-HT1B Receptor-Mediated Serotoninergic Modulation of Methylphenidate-Induced Locomotor Activation in Rats

Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD

The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample

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